The general objective of this project is to define the mechanisms by which human lymphoid cells interact with antigen-presenting cells in order to produce and regulate immune responses. Over the past year there have been three major efforts underway that are targeted on this objective: 1) dissection of the molecular basis for T-cell recognition of antigens presented by HLA class I molecules; 2) role of CD4- and CD8-associated p56lck in activation of T cells by antigen-presenting cells; and 3) continued analysis of the potential roles of human T-cell receptor alpha and beta chain genes and HLA genes in susceptibility to multiple sclerosis. The principle findings are as follows: 1) four different class I molecules, HLA-A2, HLA-A3, HLA-B27, and HLA-B37 have largely nonoverlapping peptide binding specificities as assessed by peptide competition assays; 2) the 45 pocket of HLA-A2, which is a recessed cavity that extends from the peptide-binding groove, plays a role in presentation of viral antigens and alloantigens to T cells; and 3) antigen presentation results in the rapid activation of CD4- and CD8-associated p56lck, and the phosphorylation of T-cell proteins on tyrosine residues can be mimicked by coengagement of CD4 and CD3 in a single cell system.